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Abstract

We present a 69-year-old woman with a chief complaint of postmenopausal bleeding.
She was diagnosed as having an endometrioid adenocarcinoma by biopsy, and underwent
a total abdominal hysterectomy. At the time of surgery, granulation tissue-like nodules
were found on the peritoneal serosa of the uterus. In the intraoperative cytology
of peritoneal washing, atypical cells were noted. The intraoperative frozen section
of the peritoneal nodule revealed granulation tissue with proliferating mesothelial
cells. Microscopic examination of the permanent section showed keratin granulomas
without viable adenocarcinoma cells on the serosal surface of the ovaries, fallopian
tubes and broad ligaments. Postoperative chemotherapy was administered. She has been
alive with no evidence of recurrence for 6 months postoperatively. It should be noted
that the prognosis of cases in peritoneal keratin granuloma without viable cancer
cells is favorable, and that the histological examination is essential for its diagnosis.

Keywords:

Background

Peritoneal keratin granuloma has been described in cases of endometrioid adenocarcinoma
with squamous differentiation of the uterus, ovary and atypical polypoid adenomyoma,
although the number is limited [1-9]. These cases may resemble tumor implants grossly and microscopically, and most cases
have been described as keratin granulomas without viable tumor cells. Keratin granulomas
without viable cancer cells do not show any significant prognostic influence, although
the number of cases is limited and the follow-up period is short [2]. In only rare cases, viable adenocarcinomatous cells are found in keratin granulomas
[2,6]; however, the treatment in such cases is not established. Here, we report a case
of peritoneal keratin granuloma with endometrioid adenocarcinoma of the uterine corpus
and review the literature.

Case presentation

A 69-year-old Japanese woman with no previous medical history presented with postmenopausal
bleeding. Her first period started at the age of 16, and stopped at the age of 50.
She was gravida 2, para 2 (both of them were vaginal deliveries). Cytology and biopsy
of the endometrium were obtained, which revealed endometrioid adenocarcinoma. Laboratory
data showed no abnormal findings except for the elevation of CA125 (138.2 U/mL, normal
< 35.0 U/mL). Total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymph
nodes dissection as well as the biopsy of the greater omentum were performed. Atypical
cells were noted in the intraoperative cytology of the peritoneal washing (Figure
1). In addition, peritoneal nodules suspicious for dissemination were found. However,
it turned out to be granulation tissue with proliferating mesothelial cells in the
intraoperative frozen section as well as its permanent section.

Histologically, the tumor of the uterine corpus showed diffusely proliferating atypical
endometrial glands. Squamous differentiation was also noted (Figure 2). There was no solid growth, and a diagnosis of endometrioid adenocarcinoma (Grade
1) was made. The tumor invaded beyond a half of the myometrium and extended to the
uterine cervix (FIGO IIb). Lymph node metastasis was not found.

Postoperative chemotherapy was administered, and she has been alive with no evidence
of recurrence for 6 months postoperatively.

Discussion

Granulomatous inflammation of the peritoneum has been described in cases of nonneoplastic
conditions, such as fungal or bacterial infections, ruptured dermoid cyst, previous
surgical procedure (talc and starch particles) and diagnostic tests (barium and mineral
oil) [1]. In 1961, Montes et al. reported a case of well differentiated adenocarcinoma of
the uterine corpus with foreign body keratin granulomas, and named it "cholesteatomatous
endometriosis" [3]. In 1978, Chen et al. reported five cases of uterine adenoacanthoma with peritoneal
foreign body granulomas to keratin [1]. After that, two additional cases associated with an adenosquamous carcinoma and
adenoacanthoma of the uterus were reported in 1984 [5] and 1989, respectively [6].

Histologically, keratin granulomas are composed of eosinophilic laminated keratin
surrounded by multinucleated giant cells, histiocytes, lymphocytes and plasma cells.
Keratin is associated with ghost squamous cells in which the nuclei have been lost.
These keratin materials are speculated to be refluxed from the uterine tumor through
the fallopian tubes toward the peritoneum because keratin clumps are often found within
the lumen of the fallopian tubes. In addition, many peritoneal keratin granulomas
are found around the tubal fimbriae [6].

It is important to recognize keratin granulomas because they resemble metastatic carcinoma
or other granulomatous lesion macroscopically. Microscopically, keratin granulomas
may be confused with dissemination, since reactive mesothelial cells near the keratin
granulomas may proliferate to form papillary or glandular structures [8]. In peritoneal washing cytology, it may be difficult to distinguish between reactive
mesothelial cells and tumor cells. In our case, atypical cells of peritoneal washing
were subjected to immunohistochemical stain later. Although they were negative for
calretinin and CEA, they were most likely reactive mesothelial cells than adenocarcinoma
cells.

Peritoneal keratin granulomas have been reported in cases of endometrioid adenocarcinoma
with squamous differentiation of the uterine corpus, ovary, and atypical polypoid
adenomyoma [1-9]. To our knowledge, only 24 cases of keratin granuloma with endometrioid adenocarcinoma
of the uterine corpus have been reported in the English literature (see Additional
File 1). Kim et al. reported four cases with synchronous carcinomas of the endometrium and
the ovary; however, we excluded these cases because it is uncertain whether the keratin
came from the uterus or the ovary [2].

Additional file 1.Clinicopathological features of reported cases of keratin granuloma with endometrioid
adenocarcinoma of the uterine corpus. The table shows reported 24 cases of keratin granuloma with endometrioid adenocarcinoma
of the uterine corpus.

In general, the most common location of granulomas in gynecologic specimens is the
surface of the ovary, followed by the serosal surface of the fallopian tube. Postoperative
treatments including radiation or chemotherapy were performed in 6 of the cases, and
twelve cases were treated with only surgery. One case was treated with surgery and
intraperitoneal administration of carboplatin. Clinical follow-up is available for
19 cases. Among them, only one case treated with surgery alone showed a recurrence
after a 3-years follow-up, but the patient has been free of the disease for further
10 years afterwards [1]. None of the cases died of the disease.

In three cases with endometrioid adenocarcinoma, viable tumor cells were observed
in keratin granulomas [2,6]. These lesions should be regarded as conventional metastatic foci [1]; however, the prognostic significance has not been confirmed because of the short
follow-up period. On the other hand, peritoneal keratin granulomas without viable
tumor cells do not influence the staging or the prognosis of the primary carcinoma.
Therefore, they should not be regarded as an indicator of metastatic spread [1-4]. Only one case reported that adenocarcinomatous cells were detected by careful pathologic
examination in an ovarian endometrioid adenocarcinoma [7], which suggests that extensive samplings are essential in the evaluation of these
cases.

Conclusions

Keratin granulomas with endometrioid adenocarcinoma of the uterine corpus resemble
a dissemination of tumor cells macro- and microscopically. Keratin granulomas without
tumor cells have no significant influences for the prognosis, although the number
of these cases and the lengths of the follow-up period are limited. Further studies
are needed to establish the significance of keratin granuloma with adenocarcinomatous
cells.

Consent

Written informed consent was obtained from the patient for publication of this Case
Report and any accompanying images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

KU drafted the manuscript. MS participated in the design of study. MY, IT, HY, KN,
HK, AS and SM helped to draft the manuscript. All authors read and approved the final
manuscript.